Gpr12: a novel factor for addiction and mental health

Gpr12：成瘾和心理健康的新因素

基本信息

批准号：
9813292
负责人：
Thomas Arthur Green
金额：
$ 15.8万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813292
关键词：
Affect Animal Model Anxiety Atlases Behavior Behavioral Behavioral Paradigm Brain Brain region Cells Cocaine Cocaine Dependence Complement Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Methylation Data Data Set Development Disease Disease model Dopamine D1 Receptor Electrophysiology (science)Ensure G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GPCR Signaling Pathway GPR12 gene Gene Expression Genes Genomic approach Goals Grant Histones Human Genome Ion Channel Protein Major Depressive Disorder Manuscripts Mediating Mental Depression Mental Health MicroRNAs Modeling Nature Neurons Nucleus Accumbens Pathway interactions Phenotype Pilot Projects Preparation Protein Kinase Proteins Proteome PubMed Qualifying Rattus Rodent Role Schizophrenia Science Seeds Self Administration Signal Transduction Signaling Protein Slice Specificity Sucrose Synaptic Transmission System Testing Therapeutic Therapeutic Uses Transcript Validation Viral Vector Work activating transcription factor 3 addiction adeno-associated viral vector base behavior test cocaine use demethylation druggable target environmental enrichment for laboratory animals experimental study forced swim test functional genomics innovation knock-down new therapeutic target novel novel therapeutics patch clamp pre-clinical preference response small hairpin RNA therapeutic candidate therapeutic development therapeutic target therapy development tool transcription factor transcriptome sequencing transcriptomics vector

项目摘要

ABSTRACT The development of pharmacotherapeutics for cocaine use disorder has lagged behind development of therapies for other psychiatric conditions such as depression, anxiety or schizophrenia due in large part to a lack of novel therapeutic targets. The current project is in response to RFA-RM-18-021 entitled “Pilot Projects Investigating Understudied G Protein-Coupled Receptors, Ion Channels, and Protein Kinases”. Our target, the G-protein coupled receptor Gpr12, has a PubMed score of 13.55 and a PubTater score of 8.24, qualifying this target as a very understudied yet druggable target. In response to the RFA, this project will use our novel viral vector to validate addiction- and/or depression-related changes in rodent behavioral and electrophysiological models. Gpr12 was identified via regional topographical differences in gene expression in the nucleus accumbens shell (shNAc) as part of an innovative convergent functional genomics approach. The regional expression analysis is combined with our transcriptomic data set of transcripts regulated by cocaine and transcripts regulated by environmental enrichment, a manipulation that produces a protective addiction phenotype. The ultimate long-term goal of this project is to develop a useful novel therapeutic for cocaine addiction or depression, with the near-term objective of this specific grant being to validate this novel target in behavioral and electrophysiological paradigms. The overall hypothesis of this project is that our convergent functional genomics approach of regionally-enhanced gene expression in the shNAc (using the Allen Brain Atlas) combined with quantitative cocaine and environmental enrichment RNA-sequencing data sets will identify novel druggable targets that can be developed for therapeutic use. In support of this hypothesis, the shNAc-enhanced proteins Atf3, Htr2c, Cartpt, Cyp26b1, and Fabp5 have been validated previously. Aim 1 will test Gpr12 for its ability to regulate cocaine taking/seeking in rats, as well as depression and anxiety models that are also dependent heavily upon the shNAc. A novel shRNA adeno-associated viral vector will knock down long-term expression of Gpr12 in the shNAc prior to behavioral testing. To complement the behavioral experiments, Aim 2 will evaluate corresponding functional changes in neuronal activity/excitability after knockdown of Gpr12. The current barrier to developing novel therapeutics for this understudied target is the transition from discovery-based to hypothesis-driven science. The current project will overcome that barrier by seeding the behavioral and electrophysiological validation of this novel shNAc-enhanced target.

抽象的可卡因使用障碍药物治疗的发展落后于可卡因使用障碍的发展治疗其他精神疾病，如抑郁症、焦虑症或精神分裂症，很大程度上是由于目前的项目是针对题为“试点项目”的 RFA-RM-18-021 的响应。调查尚未研究的 G 蛋白偶联受体、离子通道和蛋白激酶”。 G 蛋白偶联受体 Gpr12 的 PubMed 分数为 13.55，PubTater 分数为 8.24，符合此要求作为对 RFA 的回应，该项目将使用我们的新型病毒。用于验证啮齿类动物行为和电生理学上成瘾和/或抑郁相关变化的载体 Gpr12 是通过细胞核内基因表达的区域性差异来识别的。伏隔壳 (shNAc) 作为创新聚合功能基因组学方法的一部分。表达分析与我们受可卡因调节的转录本的转录组数据集相结合转录本受环境富集调节，这是一种产生保护性成瘾的操作该项目的最终长期目标是开发一种有用的可卡因治疗小说。成瘾或抑郁症，这项特定拨款的近期目标是验证这一新目标该项目的总体假设是我们的趋同行为和电生理学范式。 shNAc 中区域增强基因表达的功能基因组学方法（使用 Allen Brain Atlas）结合定量可卡因和环境富集 RNA 测序数据集将确定可开发用于治疗用途的新药物靶标，以支持这一假设。 shNAc 增强蛋白 Atf3、Htr2c、Cartpt、Cyp26b1 和 Fabp5 之前已得到验证 Aim 1。测试 Gpr12 在大鼠以及抑郁和焦虑模型中调节可卡因吸食/寻求的能力也严重依赖 shNAc 一种新型 shRNA 腺相关病毒载体会敲除。在行为测试之前下调 shNAc 中 Gpr12 的长期表达。实验中，目标 2 将评估神经活动/兴奋性的相应功能变化 Gpr12 的敲低目前针对这一待研究靶点开发新疗法的障碍是当前的项目将通过以下方式克服这一障碍：从基于发现的科学转向假设驱动的科学。为这种新型 shNAc 增强靶点的行为和电生理学验证奠定基础。